WO2011075481A1 - Dispositifs intracamérulaires pour administration prolongée - Google Patents

Dispositifs intracamérulaires pour administration prolongée Download PDF

Info

Publication number
WO2011075481A1
WO2011075481A1 PCT/US2010/060314 US2010060314W WO2011075481A1 WO 2011075481 A1 WO2011075481 A1 WO 2011075481A1 US 2010060314 W US2010060314 W US 2010060314W WO 2011075481 A1 WO2011075481 A1 WO 2011075481A1
Authority
WO
WIPO (PCT)
Prior art keywords
intracameral
delivery device
therapeutic agent
agent delivery
therapeutic
Prior art date
Application number
PCT/US2010/060314
Other languages
English (en)
Inventor
Michael R. Robinson
Orilla Werhner
Zoran Novakovic
James Burke
Alazar Ghebremeskel
Lon Spada
Original Assignee
Allergan, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Allergan, Inc. filed Critical Allergan, Inc.
Priority to EP10799173.9A priority Critical patent/EP2512389B1/fr
Priority to US13/511,548 priority patent/US20120245505A1/en
Publication of WO2011075481A1 publication Critical patent/WO2011075481A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
    • A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/00781—Apparatus for modifying intraocular pressure, e.g. for glaucoma treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes

Definitions

  • the present invention relates to intracameral sustained release devices and methods of using the same.
  • intraocular injection such as intravitreal injections
  • intraocular injection techniques may result in retinal detachment, physical damage to the lens, exogenous endophthalmitis, and also may result in high pulsed concentrations of therapeutic agent at the lens and other intraocular tissues.
  • ocular hypertensive agents are used to treat such conditions.
  • Ocular hypertensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as pre-surgical adjuncts.
  • Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
  • the underlying causes of primary glaucoma are not yet known.
  • the increased intraocular tension is due to the obstruction of aqueous humor outflow.
  • chronic open-angle glaucoma the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded.
  • acute or chronic angle- closure glaucoma the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupillary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity and should be treated accordingly.
  • Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber of the eye into the anterior chamber and subsequently, into the canal of Schlemm.
  • Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe and may plug the drainage channel with exudates.
  • Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
  • glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision.
  • topical agents specifically beta-adrenoreceptor antagonists, have traditionally been the method of choice for treating glaucoma.
  • prostaglandins are highly effective ocular hypotensive agents and are ideally suited for the long-term medical management of glaucoma. Although the precise mechanism is not yet known, recent experimental results indicate that the prostaglandin-induced reduction in intraocular pressure results from increased uveoscleral outflow.
  • exemplary prostaglandins include PGF 2a , PGFi a , PGE 2 , and certain lipid-soluble esters, such as Ci to C 5 alkyl esters, e.g. 1 -isopropyl esters of such compounds.
  • prostaglandins in particular PGE 2 and PGF 2a , and Ci to C 5 alkyl esters of the latter, possess ocular hypotensive activity and are recommended for use in glaucoma management.
  • the isopropyl ester of PGF2a has been shown to have significantly greater hypotensive potency than the parent compound, which was attributed to its more effective penetration through the cornea.
  • prostaglandins appear to be devoid of significant intraocular side effects
  • ocular surface (conjunctiva) hyperemia and foreign-body sensation have been consistently associated with the topical ocular use of such compounds, in particular PGF 2a and its prodrugs, e. g. its 1 -isopropyl ester, in humans.
  • the clinical potential of prostaglandins in the management of conditions associated with increased ocular pressure, e. g. glaucoma, is greatly limited by these side effects.
  • prostaglandins and their analogs, prodrugs and derivatives such as the PGF 2a derivative latanoprost, sold under the trademark XALATAN ® (Pfizer Health AB Corporation, Sweden), have been established as compounds useful in treating ocular hypertension and glaucoma.
  • latanoprost the first prostaglandin approved by the United States Food and Drug Administration for this indication, is a prostaglandin derivative possessing the undesirable side effect of producing an increase in brown pigment in the iris of 5-15% of human eyes. The change in color results from an increased number of melanosomes (pigment granules) within iridial melanocytes. While it is still unclear whether this effect has additional and deleterious clinical ramifications, from a cosmetic standpoint alone, such side effects are undesirable.
  • Certain cyclopentane heptanoic acids for example, 2-cycloalkyl or arylalkyl compounds can also be used as ocular hypotensives. These compounds, which can properly be characterized as hypotensive lipids, are effective in treating ocular hypertension.
  • the prostamide analog bimatoprost has been discovered to be effective in reducing intraocular pressure possibly by increasing the aqueous humor outflow of an eye.
  • Bimatoprost is an analog of a naturally occurring prostamide. Bimatoprost is available in a topical ophthalmic solution under the tradename LUMIGAN ® (Allergan, Inc., Irvine, CA).
  • Each milliliter of the solution contains 0.3 mg of bimatoprost as the active agent, 0.05 mg of benzalkonium chloride (BAK) as a preservative, and sodium chloride, sodium phosphate, dibasic, citric acid, and purified water as inactive agents.
  • BAK benzalkonium chloride
  • prostaglandins in addition to their ocular side effects, may possess extremely short intraocular half-lives, and thus, may pose a challenge to the formulation of controlled delivery systems.
  • prostaglandins given by intraocular administration, let alone intraocular implants are very rare and quite difficult to formulate.
  • implantable intracameral therapeutic agent delivery devices and systems to an eye, including intraocular implants, and methods of using such devices and systems that are capable of releasing a therapeutic bioactive agent at a sustained or controlled rate for extended periods of time and in amounts with few or no negative side effects.
  • the present description generally relates to intracameral therapeutic agent delivery devices and systems and therapeutic uses of such devices and systems.
  • the present description relates to intracameral, sustained release therapeutic bioactive agent delivery systems for treatment of ocular diseases and conditions.
  • the present description generally provides intracameral sustained release therapeutic agent delivery devices for the treatment of ocular diseases and conditions.
  • the devices can release at least one therapeutic bioactive agent over a relatively long period of time, for example, for at least about one week or for example, between one week and one year, such as over two weeks, one month, two months or over three months or longer, after intracameral placement.
  • intracameral placement provides both a high, local therapeutic level of at least one therapeutic bioactive agent at the target tissue and importantly eliminates or substantially eliminates presence of toxic intermediates and metabolites at the site of the target tissue.
  • intracameral therapeutic agent delivery devices comprising: a substantially cylindrical structure for at least partial placement into the anterior chamber of an eye having a first end, a second end and at least one channel traversing the substantially cylindrical structure, the structure formed of at least one biocompatible non-biodegradable material and having at least one protrusion on an outside surface that prevents migration of the device once implanted and wherein at least one of the first end and the second ends is beveled; a sustained release material associated with at least a portion of the at least one channel; and at least one therapeutic bioactive agent associated with the sustained release material.
  • FIG. 1 Further described herein are methods of treating an ocular condition comprising the steps of: providing an intracameral therapeutic agent delivery device as described herein; implanting the intracameral therapeutic agent delivery device in an eye wherein at least a portion of the intracameral therapeutic agent delivery device extends into the anterior chamber of the eye; allowing sufficient time for the therapeutic bioactive agent to migrate from the sustained release material out of the intracameral therapeutic agent delivery device and into the aqueous humor of the eye; and thereby treating the ocular condition.
  • the methods further include the use of an applicator to perform the implanting step.
  • sufficient time for the therapeutic bioactive agent to migrate from the sustained release material, out of the intracameral therapeutic agent delivery device and into the aqueous humor of the eye is between about 1 month and about 6 months.
  • At least one of the first end and second end is sealed with a cap or both ends are capped.
  • the cap or caps can be pierceable using a needle, (such as a needle attached to a syringe) and the cap or caps can be formed of a material such as, but not limited to, silicone.
  • a syringe and associated needle can be used, for example, to fill the at least one channel of the intracameral therapeutic agent delivery device with sustained release material comprising at least one therapeutic bioactive agent.
  • the at least one biocompatible non-biodegradable material forming the substantially cylindrical structure is a non-biodegradable polymer, a metal, a metal alloy or a combination thereof.
  • the sustained release material can be a biodegradable polymer or a polymer matrix.
  • the sustained release material can be packed into said at least one channel as an implant or coated on the inside surface of said at least one channel.
  • the devices include at least one additional channel traversing the substantially cylindrical structure.
  • the second channel can be, for example, an aqueous shunt.
  • the devices can further include at least one therapeutic bioactive agent releasing pore extending from inside the at least one channel to an environment outside the intracameral therapeutic agent delivery device.
  • the least one therapeutic bioactive agent releasing pore is disposed circumferentially, and in some embodiments symmetrically, around the substantially cylindrical structure of the device, or can be located on only a portion (e.g. starting at and ending, radially, within a continuous 180° degree portion/sweep) of the substantially cylindrical structure of the device of the instant disclosure.
  • the therapeutic bioactive agent migrates from the sustained release material, out of the intracameral therapeutic agent delivery device and into the aqueous humor of the eye through the at least one therapeutic bioactive agent releasing pore extending from inside the at least one channel to an environment outside the intracameral therapeutic agent delivery device.
  • Ocular conditions treated using the devices and methods described herein are, for example and not limited to, selected from the group consisting of aphakia, pseudophakia, astigmatism, blepharospasm, cataract, conjunctival diseases, conjunctivitis, corneal diseases, corneal ulcer, dry eye syndromes, eyelid diseases, lacrimal apparatus diseases, lacrimal duct obstruction, myopia, presbyopia, pupil disorders, refractive disorders, strabismus, glaucoma, ocular hypertension and combinations thereof.
  • Figure 1 is a cross-sectional view of an eye illustrating its features.
  • Figures 2A and 2B illustrate an exemplary intracameral therapeutic agent delivery device.
  • Figures 3A and 3B illustrate an alternate exemplary intracameral therapeutic agent delivery device.
  • the device contains the ability to bypass aqueous from the anterior chamber to the subconjunctival space.
  • Figure 4 illustrates yet another exemplary intracameral therapeutic agent delivery device.
  • Figure 5 illustrates an exemplary implantation location for the intracameral therapeutic agent delivery devices described herein.
  • Figure 6 is an enlarged view of the region outlined in Figure 5 further illustrating the exemplary implantation location.
  • Figure 7 illustrates an intracameral therapeutic agent delivery device as described herein including a reservoir.
  • Figure 8 illustrates a further exemplary intracameral therapeutic agent delivery device.
  • Figure 9 illustrates an exemplary implantation location for the intracameral therapeutic agent delivery device illustrated in Figure 8.
  • Figure 10 illustrates the use of a needle to fill an intracameral therapeutic agent delivery device.
  • Figures 1 1 A-D illustrate a series of Heidelberg retina angiograph (HRA) images of diffusion from an implanted device.
  • Figures 1 1 A-D illustrate HRA images after 2 minutes, 5 minutes, 10 minutes and 20 minutes.
  • biocompatible shall mean any material that does not cause injury or death or induce an adverse reaction when placed in intimate contact with the implanted tissues. Adverse reactions include inflammation, infection, fibrotic tissue formation, cell death, or thrombosis.
  • biodegradable polymer means a polymer or polymers which degrade in vivo, and wherein erosion of the polymer or polymers over time occurs concurrent with, or subsequent to, release of a drug or therapeutic bioactive agent.
  • biodegradable and “bioerodible” are equivalent and are used interchangeably herein.
  • a biodegradable polymer may be a homopolymer, a copolymer, or a polymer comprising more than two different polymeric units.
  • the polymer can be a gel or hydrogel type polymer, or mixtures or derivatives thereof.
  • eye region or "ocular site” means any area of the eyeball, including the anterior and posterior segment of the eye, and which generally includes, but is not limited to, any functional (e.g., for vision) or structural tissues found in the eyeball, or tissues or cellular layers that partly or completely line the interior or exterior of the eyeball.
  • areas of the eyeball in an ocular region include the anterior chamber, the posterior chamber, the vitreous cavity, the choroid, the suprachoroidal space, the conjunctiva, the subconjunctival space, the episcleral space, the intracorneal space, the epicorneal space, the sclera, the pars plana, surgically-induced avascular regions, the macula, and the retina.
  • eye condition means a disease, ailment or condition which affects or involves the eye or one of the parts or regions of the eye.
  • the eye includes the eyeball and the tissues and fluids which constitute the eyeball, the periocular muscles (such as the oblique and rectus muscles) and the portion of the optic nerve which is within or adjacent to the eyeball.
  • an anterior ocular condition is a disease, ailment or condition which affects or which involves an anterior (i.e. front of the eye) ocular region or site, such as a periocular muscle, an eye lid or an eye ball tissue or fluid which is located anterior to the posterior wall of the lens capsule or ciliary muscles.
  • an anterior ocular condition primarily affects or involves the conjunctiva, the cornea, the anterior chamber, the iris, the posterior chamber (behind the retina but in front of the posterior wall of the lens capsule), the lens or the lens capsule and blood vessels and nerve which vascularize or innervate an anterior ocular region or site.
  • an anterior ocular condition can include a disease, ailment or condition, such as for example, aphakia; pseudophakia; astigmatism; blepharospasm; cataract; conjunctival diseases; conjunctivitis; corneal diseases;, corneal ulcer; dry eye syndromes; eyelid diseases; lacrimal apparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupil disorders; refractive disorders and strabismus.
  • Glaucoma can also be considered to be an anterior ocular condition because a clinical goal of glaucoma treatment can be to reduce a hypertension of aqueous fluid in the anterior chamber of the eye (i.e. reduce intraocular pressure).
  • a posterior ocular condition is a disease, ailment or condition which primarily affects or involves a posterior ocular region or site such as choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e. the optic disc), and blood vessels and nerves which vascularize or innervate a posterior ocular region or site.
  • a posterior ocular condition is a disease, ailment or condition which primarily affects or involves a posterior ocular region or site such as choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e. the optic disc), and blood vessels and nerves which vascularize or innervate a posterior ocular region or site.
  • a posterior ocular condition can include a disease, ailment or condition, such as for example, acute macular neuroretinopathy; Behcet's disease; choroidal neovascularization; diabetic uveitis; histoplasmosis; infections, such as fungal or viral-caused infections; macular degeneration, such as acute macular degeneration, non-exudative age related macular degeneration and exudative age related macular degeneration; edema, such as macular edema, cystoid macular edema and diabetic macular edema; multifocal choroiditis; ocular trauma which affects a posterior ocular site or location; ocular tumors; retinal disorders, such as central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), retinal arterial occlusive disease, retinal detachment, uve
  • prodrug refers to a compound which is converted to a therapeutically active compound after administration, and the term should be interpreted as broadly herein as is generally understood in the art. While not intending to limit the scope of the present description, conversion may occur, for example, by hydrolysis of an ester group or some other biologically labile group. Generally, but not necessarily, a prodrug is inactive or less active than the therapeutically active compound to which it is converted. Ester prodrugs of the compounds disclosed herein are contemplated. An ester may be derived from a carboxylic acid of Ci (i.e.
  • an ester may be derived from a carboxylic acid functional group on another part of the molecule, such as on a phenyl ring. While not intending to be limiting and as an example, an ester may be an alkyl ester, an aryl ester, or a heteroaryl ester.
  • sustained release refers to the release of at least one therapeutic bioactive agent, or drug from sustained release material, e.g. biodegradable polymer, at a predetermined rate.
  • sustained release or controlled release, implies that the therapeutic bioactive agent is not released from the sustained release material sporadically in an unpredictable fashion and does not "burst" from the sustained release material upon contact with a biological environment (also referred to herein as first order kinetics) unless specifically intended to do so.
  • first order kinetics also referred to herein as first order kinetics
  • sustained release does not preclude a "burst phenomenon" associated with deployment. In some example embodiments according to the present description an initial burst of at least one therapeutic bioactive agent may be desirable followed by a more gradual release thereafter.
  • the release rate may be steady state (commonly referred to as "timed release” or zero order kinetics), that is the at least one therapeutic bioactive agent is released in even amounts over a predetermined time (with or without an initial burst phase) or may be a gradient release.
  • a gradient release implies that the concentration of therapeutic bioactive agent released from the sustained release material changes over time.
  • Sustained release my provide delivery of a therapeutic bioactive agents for up to about 1 month, up to about 3 months, up to about 6 months, up to about 1 year or up to about 5 years or longer.
  • therapeutically effective amount means a level or amount of a therapeutic bioactive agent or drug needed to treat an ocular condition, or reduce or prevent ocular injury or damage without causing significant negative or adverse side effects to the eye or a region of the eye.
  • a therapeutically effective amount of a bioactive agent is an amount that is effective in reducing at least one symptom of an ocular condition.
  • the intracameral therapeutic agent delivery devices can treat an ocular disease or condition by attaining a sustained or controlled release of at least one therapeutic bioactive agent from an implant associated with the intracameral therapeutic agent delivery devices described herein.
  • the intracameral therapeutic agent delivery devices are effective in treating or reducing at least one symptom of an ocular disease or condition, such as by increasing macular thickness, reducing retinal edema, reducing retinal vein occlusion, treating ocular hypertension or hypotension, reducing at least one symptom of glaucoma and/or by maintaining or improving visual acuity and color vision, for example.
  • the sustained release of therapeutic bioactive agents is accomplished using an intracameral therapeutic agent delivery device having substantially cylindrical structures for at least partial placement into the anterior chamber of an eye.
  • Eye 100 includes cornea 102 and iris 104, which surround anterior chamber 106. Behind iris 104 is the posterior chamber 108 including natural crystalline lens 1 10.
  • Anterior chamber 106 includes iridocorneal angle 1 12 and trabecular meshwork 1 14. Covering cornea 102 and sclera 1 16 partially is conjunctival sac 1 18.
  • the intracameral therapeutic agent delivery devices have a first end, a second end and at least one channel traversing the substantially cylindrical structure that makes up the body of the devices.
  • the substantially cylindrical structures are formed of at least one biocompatible non-biodegradable material and have at least one protrusion on an outside surface that prevents migration of said device once implanted and one of the ends of the substantially cylindrical structure is beveled.
  • the at least one protrusion can be provided alone or in conjunction with ribs 212, of which ribs 212 and the at least one protrusion 210 can extend the same distance from the outer surface of the intracameral therapeutic agent delivery device, or where one or the other of ribs 212 or the at least one protrusion 210 can extend a further distance than the other from the outer surface of the intracameral therapeutic agent delivery device.
  • a sustained release material is associated with at least a portion of a channel of the substantially cylindrical structure. Further, at least one therapeutic bioactive agent is associated with the sustained release material.
  • an intracameral therapeutic agent delivery device 200 includes substantially cylindrical structure 202 having first end 204, second end 206 and tube 208 traversing the device.
  • the device can also include at least one protrusion 210 for anchoring the device in place once implanted into a tissue.
  • first end 204 is beveled allowing insertion of first end 204 into one or more tissues.
  • ribs 212 are included near second end 206 to interact with the surrounding tissues.
  • Second end 206 can have head portion 214 having one or more suture holes 216 wherein sutures or other anchoring devices can be threaded. Second end 206 can also include optional plug 218 to plug tube 208. Head portion 214 can be provided at any angle ⁇ 220 that will accommodate implantation on, at or through a given tissue.
  • intracameral therapeutic agent delivery device 200 is implanted through cornea 102 or sclera 116 using a bevel at first end 204 so that first end 204 is within, for example, anterior chamber 106.
  • intracameral therapeutic agent delivery device 200 is inserted through sclera 116 into anterior chamber 106. Head portion 214 abuts sclera 116 and at least one protrusion 210 anchors the device inside the anterior chamber at trabecular meshwork 114.
  • intracameral therapeutic agent delivery device 200 can further include a second tube 222 traversing the device. Second tube 222 can be sealed at one or both ends; however, in an exemplary embodiment, fluid is free to flow through second tube 222 without a barrier or plug.
  • intracameral therapeutic agent delivery device 200 can be used to deliver a therapeutic bioactive agent as well as actively raise or lower intraocular pressure by liquid exchange through second tube 222. The aqueous humor in the anterior chamber can pass into the subconjunctival space.
  • a sustained-release coating or implant at the 214 position on figure 3a of an antifibrotic agent can be used.
  • the anti-fibrotic agents can be but are not limited to 5-flurouracil, mitomycin-C, and placlitaxel.
  • the sustained- release coating or implant at the 214 position would be polymer-based, for example, biodegradable polymers such as but not limited to superhydrolyzed polyvinyl alcohol, and the synthetic aliphatic polyesters of the poly-a-hydroxy acid family, which include polyglycolic acid (PGA), polylactic acid (PLA), and the PGA/PLA copolymer, polylactic- co-glycolic acid (PLGA).
  • the sustained-release coating could use nonbiodegradable polymers, such as but not limited to silicones and ethylene vinyl acetate.
  • intracameral therapeutic agent delivery device 200 can optionally have a barrier 224 at first end 204.
  • Optional plug 218 and barrier 224 can be made of the same material or a different material. Those materials can include, but are not limited to, pierceable polymers such as silicone, biodegradable polymers, biodegradable metals, non-biodegradable polymers or metals such as those used to form the device itself, and even a hinged member, such as a door.
  • an in-line valve within the substantially cylindrical structure 202 can be provided and utilized to prevent retrograde fluid flow in the intracameral therapeutic agent delivery device.
  • intracameral therapeutic agent delivery device 200 can have one or more therapeutic bioactive agents associated with tube 208 in at least region 226.
  • Region 226 can have at least one pore 228 where through therapeutic bioactive agents can pass into the surrounding tissues.
  • region 226, that is where through therapeutic bioactive agents can pass into surrounding tissues can be from about 25% to about 75%, or from about 25% to about 60%, or from about 35% to about 50% of the length of substantially cylindrical structure 202 having first end 204, second end 206 and tube 208 traversing the device.
  • At least one pore 228 can have diameters ranging from about 1 ⁇ to about 0.1 mm.
  • the therapeutic bioactive agents can be supplied in a sustained release formulation and coated onto at least a portion of the surface of intracameral therapeutic agent delivery device 200.
  • intracameral therapeutic agent delivery device 200 is coated inside tube 208. Coating the inside tube 208 can be from about 10% to about 90%, from about 20% to about 80%, from about 30% to about 70% or from about 40% to about 60% of the internal surface inside tube 208.
  • intracameral therapeutic agent delivery device 200 can further include reservoir 230 wherein one or more therapeutic bioactive agent is housed for delivery through tube 208 traversing the device.
  • Transfer tube 232 can extend from reservoir 230 to second end 206 and take the place of optional plug 218.
  • Reservoir 230 can take any form known in the art and can be actuated by a means such as a microchip (not shown) or pressure applied thereto.
  • therapeutic bioactive agents can be extruded from reservoir 230, through transfer tube 232, through tube 208 and into anterior chamber 106 through first end 204.
  • first end 204 can be plugged and the therapeutic bioactive agents can exit the device through at least one pore 228.
  • intracameral therapeutic agent delivery device 800 having substantially cylindrical structure 802 having first end 804 and second end 806 and tube 808 traversing the device.
  • the device can also include at least one protrusion 810 for anchoring the device in place once implanted into a tissue.
  • first end 804 is beveled allowing insertion of first end 804 into one or more tissues.
  • Substantially cylindrical structure 802 can be provided at any angle ⁇ 812 that will accommodate implantation on, at or through a given tissue.
  • intracameral therapeutic agent delivery device 800 is implanted into trabecular meshwork 114 or through trabecular meshwork 114 into Schlemn's canal.
  • intracameral therapeutic agent delivery device 800 is inserted into trabecular meshwork 114 and provides sustained release of at least one therapeutic bioactive agent from the device into anterior chamber 106.
  • intracameral therapeutic agent delivery device 800 can have one or more therapeutic bioactive agents associated with tube 808 in at least region 814.
  • Region 814 can contain therapeutic bioactive agents that pass into the surrounding tissues through second end 806.
  • therapeutic bioactive agents can pass through one or more pores (not shown) if second end 806 is sealed.
  • first end 804 can be sealed or unsealed depending on the device itself and location of implantation.
  • an intracameral therapeutic agent delivery device provided in accordance with the present disclosure can have a wall thickness of about 0.002 inch, which allows for maximal inner lumen area for sustained release materials, including in the form of an implant, for loading into or coated onto at least a portion, such as the inner surface, of an intracameral therapeutic agent delivery device provided in accordance with the present disclosure.
  • sustained release materials in the form of implants can be loaded into or coated on at least a portion of an intracameral therapeutic agent delivery device as described herein as an initial loading of therapeutic bioactive agent or as a "refill" when previous amounts of therapeutic bioactive agent have been substantially depleted.
  • syringe 1000 is fitted with needle 1002.
  • Intracameral therapeutic agent delivery device 1004 includes pierceable silicone end cap 1006. Needle 1002 is passed through anterior chamber 106, parallel to iris 104, through pierceable silicone end cap 1006 and into the substantially cylindrical structure 1008 of intracameral therapeutic agent delivery device 1004.
  • pierceable silicone end cap 1006 Once needle 1002 has breached pierceable silicone end cap 1006, sustained release materials can be injected into intracameral therapeutic agent delivery device 1004. Upon completion of injection, needle 1002 is removed, pierceable silicone end cap 1006 reseals itself and at least one therapeutic bioactive agent begins to provide sustained therapy to the eye.
  • needle 1004 in Figure 10 can be inserted through second pierceable silicone end cap 1010 located at second end 1012.
  • minimal ocular tissue is intercepted and patient discomfort is minimal.
  • the method used to deliver sustained release materials to intracameral therapeutic agent delivery devices described herein are at the discretion of the attending physician.
  • the relative average molecular weight of the polymers chosen to form the implants and coatings is the relative average molecular weight of the polymers chosen to form the implants and coatings.
  • Molecular weight of a polymer is mathematically related to the polymers mean viscosity, and therefore, different molecular weights of the two partitioned phases or polymers are included to modulate the release profile.
  • Suitable polymers for use in forming the implants and/or sustained release formulations associated with the intracameral therapeutic agent delivery devices described herein include those which are biocompatible with the eye so as to cause no substantial interference with the functioning or physiology of the eye. Such polymers preferably are at least partially, and more preferably, substantially completely biodegradable or bioerodible.
  • the polymers may be addition or condensation polymers. Generally, besides carbon and hydrogen, the polymers can include at least one oxygen.
  • the oxygen may be present as oxy, e.g. hydroxy or ether, carbonyl, e.g. non-oxo-carbonyl, such as carboxylic acid ester, and the like.
  • Useful bioerodible polymers include poly(D,L-lactide-co-glycolide) (PLGA), poly(D,L-lactide) (PLA), polyesters, poly(ortho ester), poly(phosphazine), poly (phosphate ester), poly( -caprolactone) (PCL), natural polymers such as gelatin or collagen, or polymeric blends.
  • PLGA poly(D,L-lactide-co-glycolide)
  • PLA poly(D,L-lactide)
  • polyesters poly(ortho ester), poly(phosphazine), poly (phosphate ester), poly( -caprolactone) (PCL)
  • natural polymers such as gelatin or collagen, or polymeric blends.
  • PLGA is used and the rate of biodegradation is controlled by the ratio of glycolic acid to lactic acid.
  • the most rapidly degraded copolymer has roughly equal amounts of glycolic acid and lactic acid.
  • Homopolymers, or copolymers having ratios other than equal, are more resistant to degradation.
  • the ratio of glycolic acid to lactic acid will also affect the brittleness of the resulting polymer.
  • the percentage of polylactic acid in the PLGA copolymer can be 0-100%, preferably about 15-85%, more preferably about 35-65%. In some exemplary implants, a 50:50 PLGA copolymer is used.
  • Some preferred characteristics of the polymers or polymeric materials for use in the implants and/or sustained release formulations described herein may include biocompatibility with the selected therapeutic bioactive agent, ease of use of the polymer in making the therapeutic agent delivery systems, a half-life in the physiological environment of at least about 6 hours, preferably greater than about one day, and water insolubility.
  • At least one therapeutic bioactive agent from a biodegradable polymer is the consequence of several mechanisms or combinations of mechanisms. Some of these mechanisms include desorption from the implant surface, dissolution, diffusion through porous channels of the hydrated polymer and erosion. Erosion can be bulk or surface or a combination of both.
  • therapeutic bioactive agents are released for no more than about 3-30 days after administration.
  • an implant may comprise at least one therapeutic bioactive agent and the implant associated with the intracameral therapeutic agent delivery device degrades at a rate effective to sustain release of a therapeutically effective amount for about one month after being placed within the eye.
  • the implants and/or sustained release formulations can comprise a PLA polymer having a first mean viscosity, a 50:50 PLGA polymer having a second mean viscosity and at least one therapeutic bioactive agent.
  • the PLA polymer has a mean viscosity between about 0.25 and about 0.35 dl/g or about 1 .3 dl/g and about 1 .7 dl/g and the PLGA polymer has a mean viscosity between about 0.16 and about 0.44 dl/g.
  • the mean viscosities identified above may be determined in 0.1 % chloroform at 25°C.
  • the implants and/or sustained release formulations comprise a PLA polymer having a first molecular weight, a 50:50 PLGA polymer having a second molecular weight and at least one therapeutic bioactive agent.
  • the first molecular weight is at least equal to or greater than the second molecular weight.
  • the first molecular weight is at least three times greater than the second molecular weight.
  • the first molecular weight is at least four, five or ten times greater than the second molecular weight.
  • the difference in molecular weight between the PLA and PLGA polymers allow the resulting implant and/or sustained release formulation to remain stable once formed and provides the in vivo characteristics sought.
  • the PLA polymer can have a molecular weight between about 300,000 and about 100,000 Da and the PLGA polymer can have a molecular weight between about 80,000 and about 10,000 Da.
  • the PLA and PLGA polymers form two different phases within the implant and/or sustained release formulation and the at least one therapeutic bioactive agent partitions itself into one phase or the other.
  • the at least one at least one therapeutic bioactive agent such as a prostaglandin, for example, partitions itself into the PLGA phase.
  • the implants and/or sustained release formulations associated with the intracameral therapeutic agent delivery devices described herein are developed based upon the discoveries that: (1 ) even though therapeutic bioactive agents can be eliminated from the eye extremely rapidly with short half-lives, it is theoretically feasible to deliver therapeutic bioactive agents to ocular tissues at therapeutic levels over a period of, for example, one week, or for a period of time between about 2 months and about a year; (2) systemic therapeutic bioactive agents can cause negative vision effects; (3) the negative vision effects of systemic administration are probably a result of metabolites generated by hepatic metabolism; (4) a method for the intraocular delivery of therapeutic bioactive agents for the treatment of intraocular diseases is feasible; (5) a method to reduce the intraocular toxicity of locally delivered therapeutic bioactive agents is feasible; and (6) compositions of bioerodible polymeric implants and/or sustained release formulations associated with intracameral therapeutic agent delivery devices as described herein, and therapeutic bioactive agents for the treatment of ocular diseases and conditions, can be prepared.
  • the intracameral therapeutic agent delivery devices and associated implants disclosed herein can also be configured to prevent or treat diseases or conditions, such as the following: maculopathies/retinal degeneration: macular degeneration, including age related macular degeneration (ARMD), such as non-exudative age related macular degeneration and exudative age related macular degeneration, choroidal neovascularization, retinopathy, including diabetic retinopathy, acute and chronic macular neuroretinopathy, central serous chorioretinopathy, and macular edema, including cystoid macular edema, and diabetic macular edema.
  • AMD age related macular degeneration
  • choroidal neovascularization retinopathy, including diabetic retinopathy, acute and chronic macular neuroretinopathy, central serous chorioretinopathy, and macular edema, including cystoid macular edema, and diabetic macular edema.
  • Uveitis/retinitis/choroiditis acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis, toxoplasmosis), uveitis, including intermediate uveitis (pars planitis) and anterior uveitis, multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpignous choroiditis, subretinal fibrosis, uveitis syndrome, and Vogt-Koyanagi-Harada syndrome.
  • MMWDS multiple evanescent white dot syndrome
  • Vascular diseases/exudative diseases retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), frosted branch angitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, Eales disease.
  • CAD carotid artery disease
  • Traumatic/surgical sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, laser, PDT, photocoagulation, hypoperfusion during surgery, radiation retinopathy, bone marrow transplant retinopathy.
  • Proliferative disorders proliferative vitreal retinopathy and epiretinal membranes, proliferative diabetic retinopathy.
  • Infectious disorders ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associated with HIV infection, uveitic disease associated with HIV Infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis.
  • POHS presumed ocular histoplasmosis syndrome
  • retinitis pigmentosa systemic disorders with associated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Bests disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti's crystalline dystrophy, pseudoxanthoma elasticum.
  • Retinal tears/holes retinal detachment, macular hole, giant retinal tear.
  • Tumors retinal disease associated with tumors, congenital hypertrophy of the RPE, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, intraocular lymphoid tumors.
  • Miscellaneous punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, acute retinal pigment epithelitis and the like.
  • the release of therapeutic bioactive agent from an implant, out of the intracameral therapeutic agent delivery device and into the anterior chamber, may include an initial burst of release followed by a gradual increase in the amount released, or the release may include an initial delay in release, followed by an increase in release.
  • the percentage of therapeutic bioactive agent that has been released is about one hundred percent.
  • the intracameral therapeutic agent delivery devices and associated implants described herein do not release substantially all, or about 100%, of the therapeutic bioactive agents, until after being placed in an eye for about one week or more.
  • a therapeutic bioactive agent may be desirable to provide a relatively constant rate of release of a therapeutic bioactive agent from the intracameral therapeutic agent delivery device over the life of an implant and/or sustained release formulation.
  • a therapeutic bioactive agent may be released in an amount from about 0.01 pg to about 2 pg per day for the life of the implant.
  • the release rate may change to either increase or decrease depending on the formulation of the biodegradable polymer matrix.
  • the release profile of a therapeutic bioactive agent may include one or more linear portions and/or one or more non-linear portions.
  • the release rate is greater than zero once the implant and/or sustained release formulation has begun to degrade or erode.
  • therapeutic bioactive agents form about 1 % to about 90% by weight of the implants and/or sustained release formulations; more preferably, from about 5% to about 30% by weight of the implants and/or sustained release formulations.
  • a therapeutic bioactive agent comprises about 10% by weight of an implant and/or sustained release formulation.
  • a therapeutic bioactive agent comprises about 20% by weight of an implant and/or sustained release formulation.
  • an implant and/or sustained release formulation associated with an intracameral therapeutic agent delivery device as described herein can release about 1 % a therapeutic bioactive agent, that is, of the total therapeutic bioactive agent contained therein, per day.
  • the implants and/or sustained release formulations may have a release rate of about 0.7% per day of the total therapeutic bioactive agent contained therein, when measured in vitro.
  • about 30% of a therapeutic bioactive agent comprising an implant and/or sustained release formulation associated with an intracameral therapeutic agent delivery device may have been released.
  • the total weight of implant and/or sustained release formulation in a single dosage associated with a intracameral therapeutic agent delivery device as described herein is an amount dependent on the volume of the substantially cylindrical structure and the activity or solubility of the at least one therapeutic bioactive agent.
  • the dose is about 0.1 mg to about 200 mg per implant.
  • a single intracameral therapeutic agent delivery device may contain about 1 mg, 3 mg, or about 5 mg, or about 8 mg, or about 10 mg, or about 100 mg or about 150 mg, or about 175 mg, or about 200 mg, or any useful range/amount therebetween, of implant and/or sustained release formulation, including the incorporated therapeutic bioactive agents.
  • the implants disclosed herein may have a diameter size of between about 5 ⁇ and about 1 mm, or between about 10 m and about 0.8 mm for administration with a needle.
  • the implants may have any appropriate dimensions so long as the longest dimension permits the implant to move through a needle.
  • the implants may be of any particulate geometry including micro- and nano- spheres, micro- and nano-particles, spheres, powders, rods, fragments, cubes, pills, disks, films, and the like.
  • the upper limit for size will be determined by factors such as toleration for the implant, size limitations on insertion, desired rate of release, ease of handling, and for fitting into the intracameral therapeutic agent delivery device and taught herein.
  • Spheres may be in the range of about 0.5 ⁇ to 4 mm in diameter, with comparable volumes for other shaped particles.
  • the implants may have a maximum cross-section less than about 200 ⁇ .
  • the implants have an average or mean cross-section less than about 50 ⁇ .
  • the cross-section ranges from about 30 ⁇ to about 50 ⁇ .
  • the diameters of the implants can range from 0.1 ⁇ to 1 mm.
  • the implants in one embodiment, can be formed as films to be inserted into the intracameral therapeutic agent delivery devices described herein. In order to reduce the overall dimensions of the implants when formed as films, they can be rolled up and inserted into the substantially cylindrical structure of the intracameral therapeutic agent delivery devices. Once inserted, the rolled up films can unroll either fully or partially within the confines of the devices, causing no damage to the intracameral therapeutic agent delivery devices themselves or to surrounding ocular tissue. [0092]
  • the size and form of the implant can also be used to control the rate of release, period of treatment, and therapeutic bioactive agent concentration at the site of intracameral therapeutic agent delivery device placement. Larger implants will deliver a proportionately larger dose, but depending on the surface to mass ratio, may have a slower release rate.
  • the particular size and geometry of the implant is chosen to suit the activity of the therapeutic agent and the location of its target tissue.
  • the proportions of therapeutic bioactive agent, polymer, and any other modifiers may be empirically determined by formulating several implant batches with varying average proportions.
  • a United States Pharmacopeia (USP) approved method for dissolution or release test can be used to measure the rate of release (USP 23; NF 18 (1995) pp. 1790-1798).
  • USP 23; NF 18 (1995) pp. 1790-1798 For example, using the infinite sink method, a weighed sample of implants is added to a measured volume of a solution containing 0.9% NaCI in water, where the solution volume will be such that the therapeutic bioactive agent concentration after release is less than 5% of saturation. The mixture is maintained at 37°C and stirred slowly to maintain the implants in suspension.
  • the appearance of the dissolved therapeutic bioactive agent as a function of time may be followed by various methods known in the art, such as spectrophotometrically, HPLC, mass spectroscopy, etc. until the absorbance becomes constant or until greater than 90% of the therapeutic bioactive agent has been released.
  • the at least one therapeutic bioactive agent can be any ophthalmically acceptable therapeutic agent or drug.
  • therapeutic bioactive agents include antihistamines, antibiotics, beta blockers, steroids, antineoplastic agents, immunosuppressive agents, antiviral agents, antioxidant agents, and mixtures thereof.
  • multiple implants can be used with two or more different therapeutic bioactive agents.
  • Prostaglandins can also be used as therapeutic bioactive agents.
  • Prostaglandin as used herein is meant to include one or more types of prostaglandin derivatives, prostaglandin analogues including prostamides and prostamide derivatives, prodrugs, salts thereof, and mixtures thereof.
  • the prostaglandin comprises a compound having the structure
  • A is an alkylene or alkenylene radical having from two to six carbon atoms, which radical may be interrupted by one or more oxide radicals and substituted with one or more hydroxy, oxo, alkyloxy or akylcarboxy groups wherein the alkyl radical comprises from one to six carbon atoms;
  • B is a cycloalkyi radical having from three to seven carbon atoms, or an aryl radical, selected from hydrocarbyl aryl and heteroaryl radicals having from four to ten carbon atoms wherein the heteroatom is selected from nitrogen, oxygen and sulfur atoms;
  • X is-OR 4 or -N(R 4 )2 wherein R 4 is selected from hydrogen, a lower alkyl radical having from one to six carbon atoms,
  • Pharmaceutically acceptable acid addition salts of the compounds described are those formed from acids which form non-toxic addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, sulfate, or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, saccharate and p-toluene sulphonate salts.
  • pharmaceutically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, sulfate, or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, gluconate, saccharate and p-toluene sulphonate salts.
  • a prostaglandin having the structure
  • y is 0 or 1
  • x is 0 or 1 and x and y are not both 1
  • the prostaglandin has the formula
  • the prostaglandin can also have the formula
  • Y 1 is CI or trifluoromethyl.
  • prostaglandins can have the following formula
  • the prostaglandin component comprises a compound having the formula
  • This compound is also known as bimatoprost and is publicly available in a topical ophthalmic solution under the tradename, LUMIGAN ® (Allergan, Inc., Irvine, CA).
  • Prostamide analogues can be used, such but not limited to bimatoprost acid, bimatoprost salt, and 17 dichlorophenyl prostamide.
  • the prostaglandin comprises a compound having the structure
  • This prostaglandin is known as latanoprost and is publicly available in a topical ophthalmic solution under the tradename, XALATAN ® .
  • the implants and/or sustained release formulations may comprise at least one therapeutic bioactive agent which comprises, consists essentially of, or consists of latanoprost, a salt thereof, isomer, prodrug or mixtures thereof.
  • Additional therapeutic bioactive agents or drugs include, without limitation, those disclosed in U.S. Pat. No. 4,327,725, columns 7-8, and the entire disclosure of which is incorporated herein by reference for all that it discloses regarding pharmacologic or therapeutic agents. Additional examples of useful therapeutic bioactive agents or drugs are discussed below.
  • Examples of useful antihistamines for use in accordance with the instant disclosure include, but are not limited to, loradatine, hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine, cyproheptadine, terfenadine, clemastine, triprolidine, carbinoxamine, diphenylpyraline, phenindamine, azatadine, tripelennarriine, dexchlorpheniramine, dexbrompheniramine, methdilazine, and trimprazine doxylamine, pheniramine, pyrilamine, chiorcyclizine, thonzylamine, and derivatives thereof.
  • antibiotics include without limitation, cefazolin, cephradine, cefaclor, cephapirin, ceftizoxime, cefoperazone, cefotetan, cefutoxime, cefotaxime, cefadroxil, ceftazidime, cephalexin, cephalothin,, cefamandole, cefoxitin, cefonicid, ceforanide, ceftriaxone, cefadroxil, cephradine, cefuroxime, ampicillin, amoxicillin, cyclacillin, ampicillin, penicillin G, penicillin V potassium, piperacillin, oxacillin, bacampicillin, cloxacillin, ticarcillin, azlocillin, carbenicillin, methicillin, nafcillin, erythromycin, tetracycline, doxycycline, minocycline, aztreonam, chloramphenicol,
  • beta blockers for use in accordance with the instant disclosure include, but are not limited to, acebutolol, atenolol, labetalol, metoprolol, propranolol, timolol, and derivatives thereof.
  • steroids examples include corticosteroids, such as cortisone, prednisolone, flurometholone, dexamethasone, medrysone, loteprednol, fluazacort, hydrocortisone, prednisone, betamethasone, prednisone, methylprednisolone, riamcinolone hexacatonide, paramethasone acetate, diflorasone, fluocinonide, fluocinolone, triamcinolone, derivatives thereof, and mixtures thereof.
  • corticosteroids such as cortisone, prednisolone, flurometholone, dexamethasone, medrysone, loteprednol, fluazacort, hydrocortisone, prednisone, betamethasone, prednisone, methylprednisolone, riamcinolone hexacatonide, paramethasone acetate, dif
  • antineoplastic drugs include, but are not limited to, adriamycin, cyclophosphamide, actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide, interferons, camptothecin and derivatives thereof, phenesterine, taxol and derivatives thereof, taxotere and derivatives thereof, vinblastine, vincristine, tamoxifen, etoposide, piposulfan, cyclophosphamide, and flutamide, and derivatives thereof.
  • immunosuppressive drugs include, but are not limited to, cyclosporine, azathioprine, tacrolimus, and derivatives thereof.
  • antiviral agents include but are not limited to, interferon gamma, zidovudine, amantadine hydrochloride, ribavirin, acyclovir, valciclovir, dideoxycytidine, phosphonoformic acid, ganciclovir, and derivatives thereof.
  • antioxidants include but are not limited to, ascorbate, alpha- tocopherol, mannitol, reduced glutathione, various carotenoids, cysteine, uric acid, taurine, tyrosine, superoxide dismutase, lutein, zeaxanthin, cryotpxanthin, astazanthin, lycopene, N-acetyl-cysteine, carnosine, gamma-glutamylcysteine, quercitin, lactoferrin, dihydrolipoic acid, citrate, Ginkgo Biloba extract, tea catechins, bilberry extract, vitamins E or esters of vitamin E, retinyl palmitate, and derivatives thereof.
  • Other therapeutic agents include squalamine, carbonic anhydrase inhibitors, alpha-2 adrenergic receptor agonists, antiparasitics, antifungals, beta-adrenergic receptor antagonists such as timolol maleate, carbonic anyhdrase inhibitors such as dorzolamide, and derivatives thereof. Combinations of any of the drugs and bioactive agents mentioned can be used according to the present description.
  • the amount of therapeutic bioactive agent or additional bioactive agent or drug employed in the implants and/or sustained release formulations will vary widely depending on the effective dosage required and the desired rate of release.
  • the therapeutic agent is at least about 1 % (w/w), or at least about 10 % (w/w) of the implant and/or sustained release formulation, and in particular embodiments, up to about 40% (w/w), or up to about about 50 % (w/w).
  • the implants disclosed herein may include or may be provided in the sustained release formulations described herein, can include effective amounts of buffering agents, preservatives and the like.
  • Suitable water soluble buffering agents include, without limitation, alkali and alkaline earth carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates and the like, such as sodium phosphate, citrate, borate, acetate, bicarbonate, carbonate and the like.
  • These agents advantageously are present in amounts sufficient to maintain a pH of the system of between about 2 to about 9 and more preferably about 4 to about 8.
  • the buffering agent may be as much as about 5% by weight of the total implant.
  • Suitable water soluble preservatives include sodium bisulfite, sodium bisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, parabens, methylparaben, polyvinyl alcohol, benzyl alcohol, phenylethanol and the like and mixtures thereof. These agents may be present in amounts of from about 0.001 % to about 5% by weight and preferably about 0.01 % to about 2% by weight of the implant and/or sustained release formulations. In one example embodiment, a benzylalkonium chloride preservative is provided in the sustained release formulations.
  • mixtures of controlled release profiles within a single implant and/or sustained release formulation or within several different implants may be utilized employing the same or different therapeutic bioactive agents.
  • a cocktail of release profiles, giving a biphasic or triphasic release with a single intracameral therapeutic agent delivery device is achieved, where the pattern of release may be greatly varied.
  • release modulators such as those described in U. S. Patent No. 5,869,079 may be included in the sustained release formulations.
  • the amount of release modulator employed will be dependent on the desired release profile, the activity of the modulator, and on the release profile of therapeutic bioactive agent in the absence of modulator.
  • Electrolytes such as sodium chloride and potassium chloride may also be included in the formulations.
  • the buffering agent or enhancer is hydrophilic, it may also act as a release accelerator. Hydrophilic additives act to increase the release rates through faster dissolution of the material surrounding the bioactive agent, which increases the surface area of the bioactive agent exposed, thereby increasing the rate of bioactive agent bioerosion.
  • a hydrophobic buffering agent or enhancer dissolves more slowly, slowing the exposure of bioactive agent, and thereby slowing the rate of bioactive agent bioerosion.
  • Various techniques may be used in producing the implants described herein.
  • Useful techniques include, but are not necessarily limited to, self-emulsification methods, super critical fluid methods, solvent evaporation methods, phase separation methods, spray drying methods, grinding methods, interfacial methods, molding methods, injection molding methods, extrusion methods, combinations thereof and the like.
  • Solvent selection will depend on the polymers and bioactive agents chosen.
  • a bioactive agent such as latanoprost, dichloromethane (DCM) is an appropriate solvent.
  • the solvent used to dissolve the polymers and bioactive agent(s) is evaporated at a temperature between about 20°C and about 30°C, preferably about 25°C.
  • the polymer can be dried at room temperature or even in a vacuum.
  • the cast polymers including therapeutic bioactive agents can be dried by evaporation in a vacuum.
  • the dissolving and casting steps form the implants because dissolving the polymers and therapeutic bioactive agents allows the system to naturally partition and form into its most natural configuration based on properties such as polymer viscosity and hence molecular weight, polymer hydrophobicity/hydophilicty, therapeutic bioactive agent molecular weight, therapeutic bioactive agent hydrophobicity/hydophilicty and the like.
  • the cast polymers can be processed into an implant using any method known in the art to do so.
  • the dried casted polymer can be cut into small pieces and extruded into rod shaped structures at a temperature between about 50°C and about 120°C, preferably about 90°C.
  • the films can simply be cast without extrusion.
  • the implants may further be formulated with or in a composition with an ophthalmically acceptable suspension, emulsion, or the like.
  • the sustained release formulations described herein can be a high viscosity, polymeric gel to reduce dispersion of one or more implants once placed within an intracameral therapeutic agent delivery device.
  • the gel has a high shear characteristic, meaning that the gel can be injected into intracameral therapeutic agent delivery device through a 25- 30 gauge needle, and more preferably through a 27-30 gauge needle.
  • a suitable gel for this purpose can be a hydrogel or a colloidal gel formed as a dispersion in water or other aqueous medium.
  • suitable gels include synthetic polymers such as polyhydroxy ethyl methacrylate, and chemically or physically crosslinked polyvinyl alcohol, polyacrylamide, poly(N-vinyl pyrolidone), polyethylene oxide, and hydrolysed polyacrylonitrile.
  • suitable hydrogels which are organic polymers include covalent or ionically crosslinked polysaccharide-based hydrogels such as the polyvalent metal salts of alginate, pectin, carboxymethyl cellulose, heparin, hyaluronate and hydrogels from chitin, chitosan, pullulan, gellan, xanthan and hydroxypropylmethylcellulose.
  • HYLAFORM ® Biomatrix, Inc., Ridgefiled, NJ
  • RESTYLANE ® HA North American Sales, Scottsdale, AZ
  • Sculptura and RADIESSE ® BioForm Medical, Inc., San Mateo, CA
  • Hyaluronic acid is a polysaccharide made by various body tissues and can also be used as a high viscosity, polymeric gel to reduce dispersion of one or more implants upon placement of an intracameral therapeutic agent delivery device within an eye.
  • U .S. patent 5,166,331 entitled “Hyaluronics acid fractions, methods for the preparation thereof, and pharmaceutical compositions containing same", discusses purification of different fractions of HA for use as a substitute for intraocular fluids and as a topical ophthalmic therapeutic agent carrier.
  • Other U.S. Patent Applications which discuss ocular uses of HA include U.S. Application Publication No.
  • the sustained release formulations utilized in accordance with the teachings of the present disclosure preferably comprise a high viscosity HA with an average molecular weight between about 1 and 4 million Daltons, and more preferably with an average molecular weight between about 2 and 3 million Daltons, and most preferably with an average molecular weight of about ( ⁇ 10%) 2 million Daltons.
  • Dry uncross-linked HA material comprises fibers or powder of commercially available HA, for example, fibers or powder of sodium hyaluronate (NaHA).
  • the HA may be bacterial-sourced NaHA, animal derived NaHA or a combination thereof.
  • the dry HA material is a combination of raw materials including HA and at least one other polysaccharide, for example, glycosaminoglycan (GAG).
  • GAG glycosaminoglycan
  • the HA compositions comprise or consist of high molecular weight HA. That is, nearly 100% of the HA material in the compositions is a high molecular weight HA.
  • High molecular weight HA means HA with a molecular weight of at least about 1 .0 million Daltons (mw > 10 6 Da ) to about 4.0 million Da (mw ⁇ 4 x 10 6 Da).
  • the high molecular weight HA in the present compositions may have a molecular weight of about 2.0 million Da (mw 2 x 10 6 Da).
  • the high molecular weight HA may have a molecular weight of about 2.8 million Da (mw 2.8 x 10 6 Da).
  • HA compositions are produced using dry, raw HA material, for example, NaHA, having a desired high/low molecular weight ratio.
  • dry, raw HA material for example, NaHA
  • the dry, raw HA material is cleaned and purified. These steps generally involve hydrating the dry HA fibers or powder in the desired high/low molecular weight ratio, for example, using pure water, and filtering the material to remove large foreign matters and/or other impurities.
  • the filtered, hydrated material is then dried and purified.
  • the high and low molecular weight NaHA may be cleaned and purified separately, or may be mixed together, for example, in the desired ratio, just prior to cross-linking.
  • the pure, dried NaHA fibers are hydrated in an alkaline solution to produce an uncross-linked NaHA alkaline gel.
  • Any suitable alkaline solution may be used to hydrate the NaHA in this step, for example, but not limited to an aqueous solution containing NaOH.
  • the resulting alkaline gel will have a pH above 7.5, for example, a pH above 8, for example, a pH above 9, for example, a pH above 10, for example, a pH above 12, for example, a pH above 13.
  • the next step in the manufacturing process comprises the step of cross-linking the hydrated, alkaline NaHA gel with a suitable cross-linking agent, for example, butanediol diglycidyl ether (BDDE).
  • BDDE butanediol diglycidyl ether
  • the step of HA cross-linking may be carried out using means known to those of skill in the art. Those skilled in the art appreciate how to optimize the conditions of cross-linking according to the nature of the HA, and how to carry out the cross-linking to an optimized degree.
  • the degree of cross-linking is at least about 2% to about 20%, for example, is about 4% to about 12%, wherein the degree of cross-linking is defined as the percent weight ratio of the cross-linking agent to HA- monomeric units in the HA composition.
  • the hydrated cross-linked, HA gel may be neutralized by adding an aqueous solution containing HCI. The gel is then swelled in a phosphate buffered saline solution for a sufficient time and at a low temperature.
  • the resulting swollen HA gel is a cohesive gel having substantially no visible distinct particles, for example, substantially no visibly distinct particles when viewed with the naked eye.
  • the gel has substantially no visibly distinct particles under a magnification of less than 35X.
  • the HA gel is now purified by conventional means for example, dialysis or alcohol precipitation, to recover the cross-linked material, to stabilize the pH of the material and remove any un-reacted cross-linking agent. Additional water or slightly alkaline aqueous solution can be added to bring the concentration of the NaHA in the composition to a desired concentration. In some embodiments, the concentration of NaHA in the composition is in a range between about 10 mg/ml to about 30 mg/ml.
  • the implants dissolved within a HA composition and associated with a intracameral therapeutic agent delivery device can provide sustained release of the at least one therapeutic bioactive agent one the intracameral therapeutic agent delivery device is properly placed in an eye.
  • the HA can delay release of the therapeutic bioactive agent by 3 months, and therefore, controlled release of the therapeutic bioactive agent can be delayed once the intracameral therapeutic agent delivery devices is implanted.
  • the HA can help achieve further fine tuning to the controlled release provide by polymers.
  • the intracameral therapeutic agent delivery devices described herein can be implanted into an eye using an applicator shaped and sized for a particular device. Applicators are known to those having ordinary skill in the art. The devices can be injected from the outside surface of the eye or can be placed within the anterior chamber from within.
  • the intracameral therapeutic agent delivery device illustrated in Figures 2-4 can be injected through the ocular tissue until second end 206 abuts against the outside surface of the ocular tissue it was injected through.
  • the intracameral therapeutic agent delivery device illustrated in Figure 8 can be in injected into the ocular tissue from inside the anterior chamber.
  • an applicator needle including the device is injected trough the ocular tissue into the anterior chamber and then further injected into, for example, the trabecular meshwork. Thereafter, the applicator can be removed completely from the ocular tissue leaving behind the thus implanted intracameral therapeutic agent delivery device.
  • a device in accordance with the present disclosure was loaded with sodium fluorescein (NaF) in a polymeric delivery implant.
  • NaF sodium fluorescein
  • a New Zealand white (NZW) rabbit had this device implanted in the sub-Tenon's space with the inner port extending into the anterior chamber.
  • the Heidelberg retina angiograph (HRA) imaging device demonstrated sustained-release of NaF into the anterior chamber of the rabbit's eye.
  • Figure 1 1 illustrates that in as little as 2 minutes after implantation, the NaF had begun to disperse into the anterior chamber. By 20 minutes, the NaF had substantially dispersed into most of the anterior chamber.
  • IOP intraocular pressure
  • the patient receives an intracameral implant as illustrated in Figure 2, the interior of which is coated with a sustained release formulation as described herein including bimatoprost. After 2 weeks, the IOP is reduced.
  • a 76 year old man has age-related macular degeneration and cataracts in both eyes.
  • the patient also has a history of cardiovascular disease and an inferior wall myocardial infarction 6 months previous.
  • the patient complains of blurry vision and metamorphopsia in the right eye and examination reveals visual acuity of 20/400 right eye, 20/32 left eye.
  • Retinal examination shows subfoveal choroidal neovascularization (CNV) (right eye wet AMD) approximately 1 disc area in size with surrounding hemorrhage and edema in the right eye.
  • CNV subfoveal choroidal neovascularization
  • the fellow's left eye shows high-risk features for developing wet AMD such as soft, amorphic appearing drusen that included the fovea but no signs of choroidal neovascularization and can be confirmed by fluorescein angiography (left eye dry AMD).
  • the patient receives an intracameral implant as illustrated in Figure 2, the interior of which was coated with a sustained release formulation as described herein including bimatoprost.
  • a sustained release formulation as described herein including bimatoprost.
  • the patient can have maintained vision in the both eyes of at least 20/32

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Ophthalmology & Optometry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Surgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nanotechnology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des dispositifs d'administration d'agent bioactif thérapeutique et/ou de médicament intracamérulaires qui comprennent une structure sensiblement cylindrique pour le placement au moins partiel dans la chambre antérieure d'un œil. Les dispositifs d'administration intracamérulaires ont un matériau à libération prolongée associé à moins une partie du dispositif et au moins un agent bioactif thérapeutique et/ou un médicament associé audit matériau à libération prolongée.
PCT/US2010/060314 2009-12-16 2010-12-14 Dispositifs intracamérulaires pour administration prolongée WO2011075481A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP10799173.9A EP2512389B1 (fr) 2009-12-16 2010-12-14 Dispositifs intracamérulaires pour administration prolongée
US13/511,548 US20120245505A1 (en) 2009-12-16 2010-12-14 Intracameral devices for sustained delivery

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US28707809P 2009-12-16 2009-12-16
US61/287,078 2009-12-16

Publications (1)

Publication Number Publication Date
WO2011075481A1 true WO2011075481A1 (fr) 2011-06-23

Family

ID=43608710

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/060314 WO2011075481A1 (fr) 2009-12-16 2010-12-14 Dispositifs intracamérulaires pour administration prolongée

Country Status (4)

Country Link
US (1) US20120245505A1 (fr)
EP (1) EP2512389B1 (fr)
TW (1) TW201143742A (fr)
WO (1) WO2011075481A1 (fr)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013123000A1 (fr) 2012-02-13 2013-08-22 Iridex Corporation Réduction de la pression intraoculaire dans l'œil à l'aide d'une agrafe tubulaire
US8715713B2 (en) 2011-04-29 2014-05-06 Allergan, Inc. Solvent cast film sustained release latanoprost implant
WO2014160278A1 (fr) * 2013-03-14 2014-10-02 Allergan, Inc. Système en polymère pour fixer des implants dans des aiguilles de seringue
US8900622B1 (en) 2004-04-30 2014-12-02 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
WO2015085234A1 (fr) * 2013-12-06 2015-06-11 Forsight Vision4, Inc. Dispositifs thérapeutiques implantables
US9101583B2 (en) 2004-04-30 2015-08-11 Allergan, Inc. Microparticles manufactured in an oil-in-water process comprising a prostamide
EP2739252A4 (fr) * 2011-08-05 2015-08-12 Forsight Vision4 Inc Administration de petites molécules à l'aide d'un dispositif thérapeutique implantable
CN105769430A (zh) * 2014-12-26 2016-07-20 易浦润（上海）生物技术有限公司 一种载药的泪小管栓子
US9474756B2 (en) 2014-08-08 2016-10-25 Forsight Vision4, Inc. Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
EP2555749B1 (fr) * 2010-04-06 2016-10-26 Allergan, Inc. Implants réservoirs à libération prolongée pour administration de médicament intracamérulaire
US9492316B2 (en) 2013-10-31 2016-11-15 Allergan, Inc. Prostamide-containing intraocular implants and methods of use thereof
WO2017059272A1 (fr) 2015-09-30 2017-04-06 Microoptx Inc. Dispositifs et procédés de traitement du syndrome de l'œil sec
US9775846B2 (en) 2004-04-30 2017-10-03 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related implants
WO2017180487A1 (fr) 2016-04-11 2017-10-19 The Regents Of The University Of Michigan Endoprothèse lacrymale dotée d'une ouverture
US9968603B2 (en) 2013-03-14 2018-05-15 Forsight Vision4, Inc. Systems for sustained intraocular delivery of low solubility compounds from a port delivery system implant
US10406168B2 (en) 2004-04-30 2019-09-10 Allergan, Inc. Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and related methods
US10507245B2 (en) 2012-07-19 2019-12-17 Luis Felipe Vejarano Restrepo Ophthalmic formulation and method for ameliorating presbyopia
EP3679908A1 (fr) * 2014-07-15 2020-07-15 ForSight Vision4, Inc. Dispositif de pose d'implant oculaire
US10736778B2 (en) 2014-12-31 2020-08-11 Microoptx Inc. Glaucoma treatment devices and methods
US10874548B2 (en) 2010-11-19 2020-12-29 Forsight Vision4, Inc. Therapeutic agent formulations for implanted devices
EP3941399A4 (fr) * 2019-03-21 2022-05-18 Microoptx Inc. Dispositifs et méthodes d'administration de médicament oculaire implantable

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7431710B2 (en) 2002-04-08 2008-10-07 Glaukos Corporation Ocular implants with anchors and methods thereof
US10206813B2 (en) 2009-05-18 2019-02-19 Dose Medical Corporation Implants with controlled drug delivery features and methods of using same
CN104887388B (zh) 2009-06-03 2018-01-09 弗赛特影像5股份有限公司 前段药物输送
US10245178B1 (en) * 2011-06-07 2019-04-02 Glaukos Corporation Anterior chamber drug-eluting ocular implant
RU2740680C2 (ru) 2011-09-14 2021-01-19 Форсайт Вижн5, Инк. Глазное вкладочное устройство и способы
US8834406B2 (en) * 2011-10-21 2014-09-16 Snyder Biomedical Corporation Biocompatible glaucoma drainage device
DE102012200411A1 (de) * 2012-01-12 2013-07-18 Geuder Ag Vorrichtung zur Verwendung in der Glaukomchirugie
WO2013116061A1 (fr) 2012-02-03 2013-08-08 Forsight Vision4, Inc. Procédés et instrument pour l'insertion et le retrait de dispositifs thérapeutiques
HUE046128T2 (hu) 2012-10-26 2020-02-28 Forsight Vision5 Inc Szemészeti rendszer gyógyszer szembe való késleltetett kibocsátására
JP6655610B2 (ja) 2014-05-29 2020-02-26 グローコス コーポレーション 制御された薬物送達機能を備えるインプラント及びそれを使用する方法
EP3283004A4 (fr) 2015-04-13 2018-12-05 Forsight Vision5, Inc. Composition d'insert oculaire d'agent pharmaceutiquement actif cristallin ou semi-cristallin
WO2017040853A1 (fr) 2015-09-02 2017-03-09 Glaukos Corporation Implants d'administration de médicament présentant capacité d'administration bidirectionnelle
WO2017053885A1 (fr) 2015-09-25 2017-03-30 Glaukos Corporation Implants lacrymaux à caractéristiques d'administration de médicament régulée et leurs procédés d'utilisation
CN109937025B (zh) 2016-04-20 2022-07-29 多斯医学公司 生物可吸收眼部药物的递送装置
WO2018231485A1 (fr) * 2017-06-13 2018-12-20 Innfocus, Inc. Systèmes, méthodes et appareils pour le traitement du glaucome
JP7220688B2 (ja) * 2020-09-16 2023-02-10 巨晰光纖股▲ふん▼有限公司 眼球排水用分流支持枠

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3919205A (en) 1972-07-17 1975-11-11 Squibb & Sons Inc Dithiocarbonylthioacetyl cephalosporin derivatives
US4327725A (en) 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
US5166331A (en) 1983-10-10 1992-11-24 Fidia, S.P.A. Hyaluronics acid fractions, methods for the preparation thereof, and pharmaceutical compositions containing same
GB2296663A (en) * 1995-01-03 1996-07-10 Ahmed Salih Mahmud Drainage device for alleviating excess ophthalmic fluid pressure
US5869079A (en) 1995-06-02 1999-02-09 Oculex Pharmaceuticals, Inc. Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents
US20050101582A1 (en) 2003-11-12 2005-05-12 Allergan, Inc. Compositions and methods for treating a posterior segment of an eye
US20050181017A1 (en) 2004-01-20 2005-08-18 Allergan, Inc. Compositions and methods for localized therapy of the eye
US20050197613A1 (en) * 2004-03-02 2005-09-08 Sniegowski Jeffry J. Implant having MEMS flow module with movable, flow-controlling baffle
US20060024350A1 (en) * 2004-06-24 2006-02-02 Varner Signe E Biodegradable ocular devices, methods and systems
US20070224278A1 (en) 2003-11-12 2007-09-27 Lyons Robert T Low immunogenicity corticosteroid compositions
US20070293872A1 (en) * 2006-06-20 2007-12-20 Minu, L.L.C. Ocular Drainage Device
US20090082321A1 (en) 2007-09-21 2009-03-26 Allergan, Inc. Steroid containing drug delivery systems
US20090149435A1 (en) 2003-11-12 2009-06-11 Zhengjun Wang Process for making a pharmaceutical composition
US20090227933A1 (en) * 2003-02-18 2009-09-10 S.K. Pharmaceuticals Optic nerve implants
WO2010088548A1 (fr) * 2009-01-29 2010-08-05 Forsight Labs, Llc Administration d'un médicament dans le segment postérieur

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7008396B1 (en) * 1999-09-03 2006-03-07 Restorvision, Inc. Ophthalmic device and method of manufacture and use
US20050119737A1 (en) * 2000-01-12 2005-06-02 Bene Eric A. Ocular implant and methods for making and using same
US7867186B2 (en) * 2002-04-08 2011-01-11 Glaukos Corporation Devices and methods for treatment of ocular disorders
US20050277864A1 (en) * 2000-04-14 2005-12-15 David Haffner Injectable gel implant for glaucoma treatment
US7708711B2 (en) * 2000-04-14 2010-05-04 Glaukos Corporation Ocular implant with therapeutic agents and methods thereof
US7431710B2 (en) * 2002-04-08 2008-10-07 Glaukos Corporation Ocular implants with anchors and methods thereof
CA2442652C (fr) * 2001-04-07 2011-01-04 Glaukos Corporation Stent de glaucome et procedes destines au traitement d'un glaucome
US7331984B2 (en) * 2001-08-28 2008-02-19 Glaukos Corporation Glaucoma stent for treating glaucoma and methods of use
US7951155B2 (en) * 2002-03-15 2011-05-31 Glaukos Corporation Combined treatment for cataract and glaucoma treatment
US20030229303A1 (en) * 2002-03-22 2003-12-11 Haffner David S. Expandable glaucoma implant and methods of use
US20040147870A1 (en) * 2002-04-08 2004-07-29 Burns Thomas W. Glaucoma treatment kit
US7963956B2 (en) * 2003-04-22 2011-06-21 Antisense Pharma Gmbh Portable equipment for administration of fluids into tissues and tumors by convection enhanced delivery technique
US7291125B2 (en) * 2003-11-14 2007-11-06 Transcend Medical, Inc. Ocular pressure regulation
JP5090742B2 (ja) * 2003-12-05 2012-12-05 インフォーカス リミテッド ライアビリティー カンパニー 改良緑内障移植デバイス
US20050194303A1 (en) * 2004-03-02 2005-09-08 Sniegowski Jeffry J. MEMS flow module with filtration and pressure regulation capabilities
US8128954B2 (en) * 2004-06-07 2012-03-06 California Institute Of Technology Biodegradable drug-polymer delivery system
US20070141116A1 (en) * 2004-12-03 2007-06-21 Leonard Pinchuk Glaucoma Implant Device
US20070118065A1 (en) * 2004-12-03 2007-05-24 Leonard Pinchuk Glaucoma Implant Device
US7594899B2 (en) * 2004-12-03 2009-09-29 Innfocus, Llc Glaucoma implant device
US7837644B2 (en) * 2004-12-03 2010-11-23 Innfocus, Llc Glaucoma implant device
CA2617040A1 (fr) * 2005-07-29 2007-02-01 Santen Pharmaceutical Co., Ltd. Systeme non invasif d'administration de medicament qui vise le tissu posterieur de l'oeil au moyen d'une composition solide
US20080027304A1 (en) * 2006-04-18 2008-01-31 Pardo Geoffrey B Intraocular pressure attenuation device

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3919205A (en) 1972-07-17 1975-11-11 Squibb & Sons Inc Dithiocarbonylthioacetyl cephalosporin derivatives
US4327725A (en) 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
US5166331A (en) 1983-10-10 1992-11-24 Fidia, S.P.A. Hyaluronics acid fractions, methods for the preparation thereof, and pharmaceutical compositions containing same
GB2296663A (en) * 1995-01-03 1996-07-10 Ahmed Salih Mahmud Drainage device for alleviating excess ophthalmic fluid pressure
US5869079A (en) 1995-06-02 1999-02-09 Oculex Pharmaceuticals, Inc. Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents
US20090227933A1 (en) * 2003-02-18 2009-09-10 S.K. Pharmaceuticals Optic nerve implants
US20070224278A1 (en) 2003-11-12 2007-09-27 Lyons Robert T Low immunogenicity corticosteroid compositions
US20090149435A1 (en) 2003-11-12 2009-06-11 Zhengjun Wang Process for making a pharmaceutical composition
US20050101582A1 (en) 2003-11-12 2005-05-12 Allergan, Inc. Compositions and methods for treating a posterior segment of an eye
US20050181017A1 (en) 2004-01-20 2005-08-18 Allergan, Inc. Compositions and methods for localized therapy of the eye
US20050197613A1 (en) * 2004-03-02 2005-09-08 Sniegowski Jeffry J. Implant having MEMS flow module with movable, flow-controlling baffle
US20060024350A1 (en) * 2004-06-24 2006-02-02 Varner Signe E Biodegradable ocular devices, methods and systems
US20070293872A1 (en) * 2006-06-20 2007-12-20 Minu, L.L.C. Ocular Drainage Device
US20090082321A1 (en) 2007-09-21 2009-03-26 Allergan, Inc. Steroid containing drug delivery systems
WO2010088548A1 (fr) * 2009-01-29 2010-08-05 Forsight Labs, Llc Administration d'un médicament dans le segment postérieur

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
USP, vol. 23, no. 18, 1995, pages 1790 - 1798

Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10064872B2 (en) 2004-04-30 2018-09-04 Allergan, Inc. Oil-in-water method for making polymeric implants containing a hypotensive lipid
US9393223B2 (en) 2004-04-30 2016-07-19 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
US10406168B2 (en) 2004-04-30 2019-09-10 Allergan, Inc. Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and related methods
US10398707B2 (en) 2004-04-30 2019-09-03 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related implants
US8900622B1 (en) 2004-04-30 2014-12-02 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
US10864218B2 (en) 2004-04-30 2020-12-15 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
US10328086B2 (en) 2004-04-30 2019-06-25 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
US9101583B2 (en) 2004-04-30 2015-08-11 Allergan, Inc. Microparticles manufactured in an oil-in-water process comprising a prostamide
US9775846B2 (en) 2004-04-30 2017-10-03 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related implants
US10166142B2 (en) 2010-01-29 2019-01-01 Forsight Vision4, Inc. Small molecule delivery with implantable therapeutic device
EP2555749B1 (fr) * 2010-04-06 2016-10-26 Allergan, Inc. Implants réservoirs à libération prolongée pour administration de médicament intracamérulaire
US11065151B2 (en) 2010-11-19 2021-07-20 Forsight Vision4, Inc. Therapeutic agent formulations for implanted devices
US10874548B2 (en) 2010-11-19 2020-12-29 Forsight Vision4, Inc. Therapeutic agent formulations for implanted devices
US9161929B2 (en) 2011-04-29 2015-10-20 Allergan, Inc. Solvent cast film sustained release latanoprost implant
US8715713B2 (en) 2011-04-29 2014-05-06 Allergan, Inc. Solvent cast film sustained release latanoprost implant
EP2739252A4 (fr) * 2011-08-05 2015-08-12 Forsight Vision4 Inc Administration de petites molécules à l'aide d'un dispositif thérapeutique implantable
WO2013123000A1 (fr) 2012-02-13 2013-08-22 Iridex Corporation Réduction de la pression intraoculaire dans l'œil à l'aide d'une agrafe tubulaire
EP2814555A4 (fr) * 2012-02-13 2015-11-25 Iridex Corp Réduction de la pression intraoculaire dans l'oeil à l'aide d'une agrafe tubulaire
US10369047B2 (en) 2012-02-13 2019-08-06 O3 Optix Llc Reduction of intraocular pressure in the eye using a tubular clip
CN104168943A (zh) * 2012-02-13 2014-11-26 艾瑞黛克斯公司 利用管状夹子减小眼睛内的眼内压
EP2814555A1 (fr) * 2012-02-13 2014-12-24 Iridex Corporation Réduction de la pression intraoculaire dans l'oeil à l'aide d'une agrafe tubulaire
US10507245B2 (en) 2012-07-19 2019-12-17 Luis Felipe Vejarano Restrepo Ophthalmic formulation and method for ameliorating presbyopia
WO2014160278A1 (fr) * 2013-03-14 2014-10-02 Allergan, Inc. Système en polymère pour fixer des implants dans des aiguilles de seringue
US9968603B2 (en) 2013-03-14 2018-05-15 Forsight Vision4, Inc. Systems for sustained intraocular delivery of low solubility compounds from a port delivery system implant
US9492316B2 (en) 2013-10-31 2016-11-15 Allergan, Inc. Prostamide-containing intraocular implants and methods of use thereof
US9980974B2 (en) 2013-10-31 2018-05-29 Allergan, Inc. Prostamide-containing intraocular implants and methods of use thereof
WO2015085234A1 (fr) * 2013-12-06 2015-06-11 Forsight Vision4, Inc. Dispositifs thérapeutiques implantables
US11337853B2 (en) 2014-07-15 2022-05-24 Forsight Vision4, Inc. Ocular implant delivery device and method
EP3679908A1 (fr) * 2014-07-15 2020-07-15 ForSight Vision4, Inc. Dispositif de pose d'implant oculaire
US10363255B2 (en) 2014-08-08 2019-07-30 Forsight Vision4, Inc. Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
US9895369B2 (en) 2014-08-08 2018-02-20 Forsight Vision4, Inc Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
US10765677B2 (en) 2014-08-08 2020-09-08 Forsight Vision4, Inc. Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
US9474756B2 (en) 2014-08-08 2016-10-25 Forsight Vision4, Inc. Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof
CN105769430A (zh) * 2014-12-26 2016-07-20 易浦润（上海）生物技术有限公司 一种载药的泪小管栓子
US10736778B2 (en) 2014-12-31 2020-08-11 Microoptx Inc. Glaucoma treatment devices and methods
EP3355983A4 (fr) * 2015-09-30 2019-06-26 Microoptx Inc. Dispositifs et procédés de traitement du syndrome de l'oeil sec
US10980667B2 (en) 2015-09-30 2021-04-20 Microoptx Inc. Eye treatment devices and methods
AU2016331925B2 (en) * 2015-09-30 2021-04-22 Microoptx Inc. Dry eye treatment devices and methods
WO2017059272A1 (fr) 2015-09-30 2017-04-06 Microoptx Inc. Dispositifs et procédés de traitement du syndrome de l'œil sec
CN108778398B (zh) * 2015-09-30 2021-12-14 迈克罗欧普提克斯股份有限公司 干眼症治疗装置和方法
CN108778398A (zh) * 2015-09-30 2018-11-09 迈克罗欧普提克斯股份有限公司 干眼症治疗装置和方法
EP3442484A4 (fr) * 2016-04-11 2019-12-11 The Regents of The University of Michigan Endoprothèse lacrymale dotée d'une ouverture
WO2017180487A1 (fr) 2016-04-11 2017-10-19 The Regents Of The University Of Michigan Endoprothèse lacrymale dotée d'une ouverture
EP3941399A4 (fr) * 2019-03-21 2022-05-18 Microoptx Inc. Dispositifs et méthodes d'administration de médicament oculaire implantable
AU2020240315B2 (en) * 2019-03-21 2023-06-29 Innomedex Llc Implantable ocular drug delivery devices and methods

Also Published As

Publication number Publication date
US20120245505A1 (en) 2012-09-27
EP2512389B1 (fr) 2015-09-02
EP2512389A1 (fr) 2012-10-24
TW201143742A (en) 2011-12-16

Similar Documents

Publication Publication Date Title
EP2512389B1 (fr) Dispositifs intracamérulaires pour administration prolongée
US10842739B2 (en) Biodegradable alpha-2 agonist polymeric implants and therapeutic uses thereof
US10328086B2 (en) Hypotensive lipid-containing biodegradable intraocular implants and related methods
US20200069847A1 (en) Prostaglandin and prostamide drug delivery systems and intraocular therapeutic uses thereof
US9775846B2 (en) Hypotensive lipid-containing biodegradable intraocular implants and related implants
AU2016228292A1 (en) Intraocular bioactive agent delivery compositon including a molecular partitioning system
MXPA06011992A (es) Implantes biodegradables intraoculares que contienen prostamidas

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10799173

Country of ref document: EP

Kind code of ref document: A1

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10799173

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 13511548

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2010799173

Country of ref document: EP